Background: There is an association between a greater adherence to a Mediterranean diet and a reduced risk of developing chronic diseases. However, it is not clear whether this dietary pattern may be protective also against the development of obesity. Objective: We assessed the association between the adherence to the Mediterranean dietary pattern (MDP), prospective weight change, and the incidence of overweight or obesity. Design: We conducted a prospective cohort study the European Prospective Investigation into Cancer and Nutrition Physical Activity, Nutrition, Alcohol Consumption, Cessation of Smoking, Eating Out of Home, and Obesity (EPIC-PANACEA) project in 373,803 individuals (103,455 men and 270,348 women; age range: 25-70 y) from 10 European countries. Anthropometric measurements were obtained at recruitment and after a median follow-up time of 5 y. The relative Mediterranean Diet Score (rMED; score range: 0-18) was used to assess adherence to the MDP according to the consumption of 9 dietary components that are characteristic of the Mediterranean diet. The association between the rMED and 5-y weight change was modeled through multiadjusted mixed-effects linear regression. Results: Individuals with a high adherence to the MDP according to the rMED (11-18 points) showed a 5-y weight change of 0.16 kg (95% CI: 0.24, 0.07 kg) and were 10% (95% CI: 4%, 18%) less likely to develop overweight or obesity than were individuals with a low adherence to the MDP (0-6 points). The low meat content of the Mediterranean diet seemed to account for most of its positive effect against weight gain. Conclusion: This study shows that promoting the MDP as a model of healthy eating may help to prevent weight gain and the development of obesity. Am J Clin Nutr 2010;92:912-21.